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Rudolf Uher

Other affiliations: Karolinska Institutet, Duke University, Medical Research Council  ...read more
Bio: Rudolf Uher is an academic researcher from Dalhousie University. The author has contributed to research in topics: Major depressive disorder & Bipolar disorder. The author has an hindex of 77, co-authored 314 publications receiving 23342 citations. Previous affiliations of Rudolf Uher include Karolinska Institutet & Duke University.


Papers
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Journal ArticleDOI
Naomi R. Wray1, Stephan Ripke2, Stephan Ripke3, Stephan Ripke4  +259 moreInstitutions (79)
TL;DR: A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent and significant loci and finds important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia.
Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

1,898 citations

Journal ArticleDOI
TL;DR: Research is reviewed about variation in the promoter region of the serotonin transporter gene (SLC6A4) and its contribution to stress sensitivity and the contribution of GxE research to the public understanding of genetic science.
Abstract: Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sen...

1,200 citations

Journal ArticleDOI
TL;DR: A meta-analysis of 16 epidemiological studies suggested that childhood maltreatment was associated with an elevated risk of developing recurrent and persistent depressive episodes and with lack of response or remission during treatment for depression.
Abstract: Objectives:Evidence suggests that childhood maltreatment may negatively affect not only the lifetime risk of depression but also clinically relevant measures of depression, such as course of illness and treatment outcome. The authors conducted the first meta-analysis to examine the relationship between childhood maltreatment and these clinically relevant measures of depression. Method:The authors conducted searches in MEDLINE, PsycINFO, and Embase for articles examining the association of childhood maltreatment with course of illness (i.e., recurrence or persistence) and with treatment outcome in depression that appeared in the literature before December 31, 2010. Recurrence was defined in terms of number of depressive episodes. Persistence was defined in terms of duration of current depressive episode. Treatment outcome was defined in terms of either a response (a 50% reduction in depression severity rating from baseline) or remission (a decrease in depression severity below a predefined clinical signifi...

1,110 citations

Journal ArticleDOI
Stephan Ripke1, Naomi R. Wray2, Cathryn M. Lewis3, Steven P. Hamilton4, Myrna M. Weissman5, Gerome Breen3, Enda M. Byrne2, Douglas Blackwood6, Dorret I. Boomsma7, Sven Cichon8, Andrew C. Heath9, Florian Holsboer, Susanne Lucae4, Pamela A. F. Madden9, Nicholas G. Martin2, Peter McGuffin3, Pierandrea Muglia8, Markus M. Noethen10, Brenda P Penninx7, Michele L. Pergadia9, James B. Potash11, Marcella Rietschel10, Danyu Lin12, Bertram Müller-Myhsok8, Jianxin Shi13, Stacy Steinberg8, Hans J. Grabe, Paul Lichtenstein14, Patrik K. E. Magnusson14, Roy H. Perlis7, Martin Preisig15, Jordan W. Smoller16, Kari Stefansson, Rudolf Uher3, Zoltán Kutalik17, Katherine E. Tansey3, Alexander Teumer, Alexander Viktorin14, Michael R. Barnes11, Thomas Bettecken18, Elisabeth B. Binder19, René Breuer10, Victor M. Castro20, Susanne Churchill13, William Coryell11, Nicholas John Craddock, Ian W. Craig3, Darina Czamara6, Eco J. C. de Geus7, Franziska Degenhardt8, Anne Farmer3, Maurizio Fava16, Josef Frank10, Vivian S. Gainer, Patience J. Gallagher16, Scott D. Gordon2, Sergey Goryachev, Magdalena Gross8, Michel Guipponi21, Anjali K. Henders2, Stefan Herms8, Ian B. Hickie22, Susanne Hoefels8, Witte J.G. Hoogendijk3, Jouke-Jan Hottenga7, Dan V. Iosifescu16, Marcus Ising9, Ian Jones2, Lisa Jones22, Tzeng Jung-Ying15, James A. Knowles18, Isaac S. Kohane16, Martin A. Kohli2, Ania Korszun9, Mikael Landén5, William Lawson19, Glyn Lewis23, Donald J. MacIntyre6, Wolfgang Maier8, Manuel Mattheisen8, Patrick J. McGrath5, Andrew M. McIntosh6, Alan W. McLean6, Christel M. Middeldorp7, Lefkos T. Middleton23, G. M. Montgomery2, Shawn N. Murphy16, Matthias Nauck, Willem A. Nolen, Dale R. Nyholt2, Michael Conlon O'Donovan24, Hogni Oskarsson, Nancy L. Pedersen14, William A. Scheftner20, Andrea Schulz, Thomas G Schulze16, Stanley I. Shyn9, Engilbert Sigurdsson, Susan L. Slager25, Johannes H. Smit7, Hreinn Stefansson17, Michael Steffens8, Thorgeir E. Thorgeirsson, Federica Tozzi, Jens Treutlein10, Manfred Uhr, Edwin J. C. G. van den Oord26, Gerard van Grootheest7, Henry Völzke14, Jeffrey B. Weilburg16, Gonneke Willemsen7, Frans G. Zitman27, Benjamin M. Neale, Mark J. Daly1, Douglas F. Levinson28, Patrick F. Sullivan12 
TL;DR: This article conducted a genome-wide association studies (GWAS) mega-analysis for major depressive disorder (MDD) using more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18,759 independent and unrelated subjects of recent European ancestry.
Abstract: Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

989 citations

Journal ArticleDOI
01 Jul 2010
TL;DR: The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans, research about one of the most extensive areas of inquiry.
Abstract: Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity...

794 citations


Cited by
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Journal Article
TL;DR: This book by a teacher of statistics (as well as a consultant for "experimenters") is a comprehensive study of the philosophical background for the statistical design of experiment.
Abstract: THE DESIGN AND ANALYSIS OF EXPERIMENTS. By Oscar Kempthorne. New York, John Wiley and Sons, Inc., 1952. 631 pp. $8.50. This book by a teacher of statistics (as well as a consultant for \"experimenters\") is a comprehensive study of the philosophical background for the statistical design of experiment. It is necessary to have some facility with algebraic notation and manipulation to be able to use the volume intelligently. The problems are presented from the theoretical point of view, without such practical examples as would be helpful for those not acquainted with mathematics. The mathematical justification for the techniques is given. As a somewhat advanced treatment of the design and analysis of experiments, this volume will be interesting and helpful for many who approach statistics theoretically as well as practically. With emphasis on the \"why,\" and with description given broadly, the author relates the subject matter to the general theory of statistics and to the general problem of experimental inference. MARGARET J. ROBERTSON

13,333 citations

Journal Article
TL;DR: For the next few weeks the course is going to be exploring a field that’s actually older than classical population genetics, although the approach it’ll be taking to it involves the use of population genetic machinery.
Abstract: So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

9,847 citations

01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,409 citations

Journal ArticleDOI
TL;DR: It is found that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size, and the LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control.
Abstract: Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

3,708 citations